Role of succinate dehydrogenase in ovarian cancer metabolism

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Chemotherapy-resistant ovarian cancer recurs in ~85% of patients and contributes to high rates of cancer-related mortality. The reprograming of cellular metabolism towards anaerobic glycolysis (the Warburg effect) is an important mechanism of chemotherapy resistance. Precision medicine targeting the unique metabolic state of cancer holds great promise to improve the efficacy of ovarian cancer treatment and reduce chemotherapy resistance. From a comprehensive analysis of metabolic pathways in our patient-derived ovarian tumors and The Cancer Genome Atlas (TCGA) data, we discovered that a key mitochondrial enzyme, succinate dehydrogenase (SDHA), is significantly upregulated in 19% of ovarian cancer patients, and is associated with significantly improved patient survival. Our preliminary studies indicate that elevated SDHA increases mitochondrial pyruvate carrier 1 (MPC1) protein expression, which increases pyruvate import to mitochondrial leading to reversal of the Warburg effect and suppression of cell proliferation. In addition, our preliminary data shows that elevated SDHA contributes to imbalance of redox systems, which may sensitize ovarian cancer cells to chemotherapy and/or agents that generate reactive oxygen species (ROS). The overall goal of this study is to determine the mechanism by which elevated SDHA alters ovarian tumor biology to take full advantage of druggable metabolic vulnerabilities such as increased sensitivity to chemotherapy and/or ROS-generating agents to improve patient survival. In Aim 1, we will determine the mechanism by which elevated SDHA reprograms cellular metabolism to regulate ovarian cancer cell proliferation. We will overexpress or knockdown SDHA in ovarian cancer cell lines followed by metabolic and functional characterization of the cells including an evaluation of glycolysis, oxygen consumption and pyruvate transport into mitochondria by Seahorse XF Technology, mass spectrometry and metabolic tracer analyses. We will explore the independent roles of elevated SDHA, SDHA substrates (succinate, fumarate), or MPC1 in reprograming of cellular metabolism and cell proliferation. In Aim 2, we will determine if elevated SDHA, by impairing cellular redox regulation, increases ovarian tumor sensitivity to chemotherapy (cisplatin/paclitaxel) and/or a ROS-generating agent (elesclomol). We will test the effect of SDHA on increasing mitochondrial-dependent respiration and ROS generation by performing respirometry analyses. Finally, we will test in vivo if SDHA-amplified ovarian tumors show better responses to chemotherapy and/or elesclomol using selected patient-derived xenografts (PDXs). The immediate contribution of this project is to explore the novel role of SDHA in changing mitochondrial energy metabolism to improve ovarian cancer patient survival by suppressing of tumor growth and/or increasing the effectiveness of chemotherapy to kill tumor cells. This study is a critical step toward our long-term goal, to develop innovative ways to precisely modulate ovarian cancer-specific metabolism to improve patients’ response to therapy and survival.